1. Field of the Invention
The present invention relates to certain compounds of the formula ##STR2## wherein the broken line is a bond or no bond, and the pharmaceutically acceptable cationic salts thereof having utility as hypoglycemic and anti-atherosclerosis agents, methods for their use and pharmaceutical compositions containing them.
2. General Background
In spite of the early discovery of insulin and its subsequent wide-spread use in the treatment of diabetes, and the later discovery and use of sulfonylureas (e.g. chlorpropamide, tolbutamide, acetohexamide, tolazamide) and biguanides (e.g. phenformin) as oral hypoglycemic agents, the treatment of diabetes remains less than satisfactory. The use of insulin, necessary in about 10% of diabetic patients in which synthetic hypoglycemic agents are not effective (Type I diabetes, insulin dependent diabetes mellitus), requires multiple daily, usually self, injection. Determination of the proper dosage of insulin requires frequent estimations of the sugar in the urine or in the blood. The administration of an excess dose of insulin causes hypoglycemia, with effects ranging from mild abnormalities in blood glucose to coma, or even death. Treatment of non-insulin dependent diabetes mellitus (Type II diabetes) usually consists of a combination of diet, exercise, oral agents, e.g., sulfonylureas, and in more severe cases, insulin. However, the clinically available hypoglycemics are unfortunately fraught with toxic manifestations which limit their use. In any event, where one of these agents may fail in an individual case, another may succeed. A continuing need for hypoglycemic agents, which may be less toxic or succeed where others fail, is clearly evident.
In addition to the hypoglycemic agents cited above, a variety of other compounds have been reported to possess this type of activity, as reviewed recently by Blank [Burger's Medicinal Chemistry, Fourth Edition, Part II, John Wiley and Sons, N.Y. (1979), pp. 1057-1080].
U.S. Pat. No. 4,342,771 discloses a class of oxazolidinedione hypoglycemic agents of the general formula ##STR3## where R.sup.a is H or certain acyl groups and R.sup.b is certain mono- or bicyclic heterocyclic groups.
U.S. Pat. No. 4,617,312 discloses a group of 5-phenylthiazolidine-2,4-dione hypoglycemic agents of the formula ##STR4## where R.sup.c is lower alkyl, X.sup.a is F, Cl or Br and Y.sup.a is H, Cl, lower alkyl or lower alkoxy.
U.S. Pat. No. 4,461,902 discloses certain 5-[(4-cyclohexylmethoxyphenyl)methyl]thiazolidine-2,4-dione hypoglycemic agents of the formula ##STR5## where R.sup.d is H or lower alkyl and Y.sup.b is an oxo or hydroxy group.
U.S. Pat. No. 4,703,052 discloses certain hypoglycemic thiazolidinediones of the formula ##STR6## or a pharmaceutically acceptable cationic salt thereof, wherein the broken line is a bond or no bond, n is zero, 1, or 2; X is O, S, ##STR7## CH.sub.2, C.dbd.O, CHOH or NR.sub.5 where R.sub.5 is H, formyl, (C.sub.2 -C.sub.5)alkanoyl, benzyloxycarbonyl, CO(CH.sub.2).sub.x C.sub.6 H.sub.5 where x is an integer from 1 to 3, (C.sub.1 -C.sub.6)alkyl, said alkyl optionally substituted by HO, Cl, Br, OCH.sub.3, phenyl or COOR.sub.6 where R.sub.6 is (C.sub.1 -C.sub.4)alkyl;
R is H, CH.sub.3 or C.sub.2 H.sub.5 ; PA1 when taken separately, R.sub.1 is H, (C.sub.5 -C.sub.7)cycloalkyl, (C.sub.6 -C.sub.8)methylsubstituted cycloalkyl, pyridyl, thienyl, furyl, naphthyl, p-biphenylyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, C.sub.6 H.sub.4 W.sub.2 or alk-W.sub.1 and alk is (C.sub.1 -C.sub.6)alkylene, ethylidene or isopropylidene; W.sub.1 is H, OH, (C.sub.1 -C.sub.4)alkoxy, (C.sub.1 -C.sub.4)thioalkyl, pyridyl, furyl, thienyl, tetrahydrofuryl, tetrahydrothienyl, naphthyl, (C.sub.5 -C.sub.7)cycloalkyl or C.sub.6 H.sub.2 W.sub.2 and W.sub.2 is H, OH, F, Cl, Br, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy or (C.sub.1 -C.sub.4)thioalkyl; R.sub.2 is H or CH.sub.3, R.sub.3 is H, (C.sub.1 -C.sub.6)alkyl, C.sub.6 H.sub.4 W.sub.2 or benzyl; and R.sub.4 is H;
when R.sub.1 and R.sub.2 are taken together they form (C.sub.4 -C.sub.6) alkylene and R.sub.3 and R.sub.4 are each H;
when R.sub.3 and R.sub.4 are taken together they form (C.sub.4 -C.sub.6)alkylene and R.sub.1 and R.sub.2 are each H; and when R.sub.2 and R.sub.3 are taken together they are (C.sub.3 -C.sub.4)alkylene and R.sub.1 and R.sub.4 are each H.
Certain 5RS racemic and 5R optically active oxazolidine-2-one compounds of the formula ##STR8## wherein R.sup.f is ##STR9##
W is sulfur or oxygen;
X and X.sup.1 are each independently H, Cl, F or CF.sub.3 ;
Y is inter alia ##STR10## R.sup.e is H or CH.sub.3 ;
and certain pharmaceutically acceptable salts thereof are disclosed in international patent application No. PCT/US87/01356 which is assigned to and has been filed in the name of the assignee hereof. That patent application also discloses the use of such compounds as hypoglycemic agents and, further, the use of some, if not all, of such compounds to lower blood cholesterol levels.
Atherosclerosis, a disease of the arteries, is recognized to be the leading cause of death in the United States and Western Europe. The pathological sequence leading to atherosclerosis and occlusive heart disease has been described in detail by Ross and Glomset in New England Journal of Medicine 295, 369-377 (1976). The earliest stage in this sequence is the formation of "fatty streaks" in the carotid, coronary and cerebral arteries and in the aorta. These lesions are yellow in color due to the presence of lipid deposits found principally within smooth-muscle cells and in macrophages of the intima layer of the arteries and aorta. Cholesterol and cholesteryl ester account for most of this lipid. Further, it is postulated that most of the cholesterol found within the fatty streaks results from uptake from the plasma. These fatty streaks, in turn, give rise to development of the "fibrous plaque", which consists of accumulated intimal smooth muscle cells laden with lipid and surrounded by extra cellular lipid, collagen, elastin and proteoglycans. The cells plus matrix form a fibrous cap that covers a deeper deposit of cell debris and more extracellular lipid. The lipid is primarily free and esterified cholesterol. The fibrous plaque forms slowly, and is likely in time to become calcified and necrotic, advancing to the " complicated lesion" which accounts for the arterial occlusion and tendency toward mural thrombosis and arterial muscular spasm that characterize advanced atherosclerosis.
Epidemiological evidence has firmly established hyperlipidemia as a primary risk factor in causing cardiovascular disease (CVD) due to atherosclerosis. In recent years, leaders of the medical profession have placed renewed emphasis on lowering plasma cholesterol levels, and low density lipoprotein cholesterol in particular, as an essential step in prevention of CVD. The upper limits of "normal" are now known to be significantly lower than heretofore appreciated. As a result, large segments of Western populations are now realized to be at high risk for development or progression of CVD because of this factor. Individuals who possess independent risk factors in addition to hyperlipidemia are at particularly high risk. Such independent risk factors include glucose intolerance, left ventricular hypertrophy, hypertension, and being of the male sex. Cardiovascular disease is especially prevalent among diabetic subjects, at least in part because of the existence of multiple independent risk factors. Successful treatment of hyperlipidemia in the general population, and in diabetic subjects in particular, is therefore of exceptional medical importance.
The first step in recommended therapeutic regimens for hyperlipidemia is dietary intervention. While diet alone produces adequate response in some individuals, many others remain at high risk and must be treated further by pharmacological means. New drugs for the treatment of hyperlipidemia are, therefore, of great potential benefit for large numbers of individuals at high risk of developing CVD. Further, successful treatment of both the hyperlipidemia and hyperglycemia associated with the diabetic state with a single therapeutic agent is particularly desirable.